Alkylation and aralkylation of organic compounds



Patented Nov. 21, 1944 UNITED STATES PATENT OFFlCE ALKYLATION ANDARALKYLATION OF ORGANIC COMPOUNDS David M. Jones, Richmond Heights, M0,,assignor to Mallinckrodt Chemical Works, St. Louis, Mo., a corporationof Missouri No Drawing. Application March 11, 1941, Serial No. 382,788

9 Claims. (Cl. 260-485) This invention relates to agents and methods forintroducing alkyl and aralkyl groups into organic compounds, and, morespecifically, into mono-substituted malonic esters.

Among the several objects of the invention may be noted the provision ofa new class of alkylating and aralkylating agents and a general processfor carrying out alkylations and aralkylations of the types indicatedwhich is characterized by its inexpensive and readily procurable rawmaterials, the ease with which. it 'may be carried out, the-simplicityof the process equipment, and the convenience of the operation. Thislatter factor is of particular advantage when alkylation or aralkylationof malonic esters produced by the processes described in the copendingapplications of Vernon H. Wallingford and August H. Homeyer, Serial No.287,001, filed July '28, 1939, and Serial No. 374,254, filed January 13,1941, isdesired.

the malonic ester may be carried out by any convenient means;advantageously by the pro- The invention accordingly comprises the stepsand sequence of steps, and featuresof synthesis, analysis, ormetathesis, which will be exemplified in the processes hereinafterdescribed, and the scope of the application of which will be indicatedin the claims.

The well-known methods for alkylating or aralkylating malonic estersgenerally involve, first, the formation of a metallo derivative of theappropriate malonic ester, and second, the reaction of this metalloderivative with an alkyl or aralkyl halide. In some cases, .alkyl oraralkyl sulfates may be the preferred alkylating or aralkylating agents.ese reactions are most frequently carried out n an alcoholic medium.--These conventional. procedures have the disadvantage that the .alkyland aralkyl halides are notcommercially available in many cases, and inany event, are relatively expensive. The chlorides, though. lessexpensive, are also less satisfactory than the more expensive bromidesand iodides, so that these reagents do not readily lend themselves toeconomy in production." 01 the dialkyl sulfates only dimethyl anddiethyl sulfate are commercially available and, as a class, the sulfates'are costly alkylating agents.

In contrast, the present invention, in many of its embodiments, providesinexpensive and readily accessible alkylating and aralkylating agentswhich can readily be made through a simple ester interchange.

Broadly speaking, the present invention comprises an entirely new;classv of alkylating and aralkylating agents and processes for theapplication of these'agents. 'In the specific examples cedure describedby Vernon H.-Wallingford and August H. Homeyer in their copendingapplications, Serial No. 287,000,-filed July 28, 1939, and Serial No.383,164, filed March 13, 1941.

While the essence of the invention resides in the reaction between themetallo derivative and the dialkyl or diaralkyl carbonate, regardless ofthe manner in which the metallo compound is formed, it is advantageousin some instances to take certain additional steps. For example, if

' the metallo compounds are prepared by the wellknown reaction of amono-substituted-malonic ester with a metal alcoholate, according to theequation:

it is in some cases advantageous to remove the product alcohol, R"OH,before the alkylation or aralkylation step is begun. In other cases thisproduct alcohol is without serious disadvantage.

Usually when vthe reaction is carried out by the use of a malonic ester,a metal alcoholate', and- The use of the dialkyl ordiaralkyl carbonateas the reaction medium, that isfcarrying out the alkylation oraralkylation in a large excess of the carbonate is a distinct advantagein this process in many cases. This is-due to both the cheapness ofthese materials and their manipulative convenience. They can be easilyrecovered and their presence inhibits side reactions. It has been found,however,'that a part of the excess carbonate can be replaced by an inertsolvent without disadvantage in some cases.

The mechanism of the reactions involved in the presentinvention has notyet been determined, but it probably closely parallels that of thewell-known alkylations of metallo derivatives of. malonic esters bydialkyl sulfates or alkyl halides.

The following examples illustrate certain speclfic'embodiments of thepresent invention, but are intended to exemplify rather than limit.

Exmru: 1

Ethylation of diethyl ethylmalonate A 1 liter, threeenecked flask wasarranged with a sealed stirrer and a five plate column. Anhydrous ethylalcohol (250 ml.) was placed in the flask and sodium (11.5 g.) wasreacted with it. Most of the excess alcohol was then distilled out at afinal pressure of 20 mm. and bath temperature of 140C. The residual,white solid cake was cooled and broken up and diethyl carbonate (400ml.) was added. The remaining excess alcohol was then fractionated outat 150 mm. pressure. Then at a bath temperature of 80 0., diethylethylmalonate (94 g.) was added. The alcohol which formed (30 ml.) wasdistilled out at 150 mm. pressure and a bath temperature of 100 C. inone-half hour along with diethyl carbonate,(40 ml.). Then, atatmospheric pressure and abath temperature of LEO-155 C., the mixturewas refluxed 'five hours. The mixture was then cooled and treated withacetic acid (30 m1) and water. The oil was washed free of acid withwater and dilute sodium carbonate solution. It was then dried withsodium sulfate and fractionated. After the diethyl carbonate. was

removed there was recovered 24% (23 g.) of the.

I EXAMPLE 2 Emulation of diethyl butylmalonate' In-this case, thesodioderivative of diethyl nbutylmalonate was prepared from ethylcaproate, by reaction with the diethyl carbonate. as described in thecopending application of Wallingford and Homeyer, Serial No. 374,254,'filed Janumy 13, 1941, and then, without isolation, this compound wasethylated with the diethyl carbonate to produce diethylethylbutylmalonate'.

A mixture was made 'of sodium ethylate (34 g.)

and diethyl carbonate (400 ml.) as described in Example 1. At a bathtemperature of 150-155 0., ethyl caproate (72 g.) was added during onehour. Ethyl alcohol (55 cc.) was formed and was fractionated out duringthree hours. The

' mixture wasthen refluxed for four hours. .The

mixture was then cooled and worked'up as described in Example 1. Therewas recovered 33% (24 g.) of the ethyl caproate. There were obtainedyieldsof 26% (28 g.) of diethyl butylmalonate and 34% '(41 g.) ofdiethyl ethylbutylmalonate. This is a 50% yield of diethyl ethylbutylmalonate based on the ethyl caproate ac utemperature of -160 C. for sixhours.

aseaooa EXAMPLE 3 Ethylation of diethyl isoamylmalonate Similarly, thesodio derivative of diethyl isoamylmalonate was prepared from ethylisoamylacetate, by reaction with diethyl carbonate, as described in thecopending application of Wallingford and Homeyer, Serial No. 374,254,filed January 13, 1941, and then this compound was ethylated withdiethylcarbonate to produce diethyl isoamylethylmalonate.

A mixture was made of sodium ethylate (16 g.) and diethyl carbonate (250ml.) as described in Example 1. Then, at a bath temperature of -160 C.,ethyl isoamylacetate (45 g.) was added. During three hours there wasfractionated out 33 ml. of ethyl alcohol. Then the mixture was refluxedthree hours at a bath tem perature of -465 C. The mixture was thencooled and worked up as described in Example 1.

There was recovered 25% (11 g.) of the et y isoamylacetate. There wasobtained a 25% 16 g.) yield of diethyl isoamylmalonate and there wasobtained a 45% (32 g.) yield of diethyl ethylisoamylmalonate. This is a60% yield of diethyl ethylisoamylmalonate based on the et ylisoamylacetate actually consumed. The boiling point of the diethylethylisoamylmalonate was 135 C. at 16 mm. pressure and the 11. 20/1) was1.4290-1.4295. The ester was identified by hydrolyzing it to obtainethylisoamylmalonic acid which melted at 120121 C.

p Exmm54 n-Butylation of di-n-butyl ethylmalonate Sodium (416 g.) wasreacted with n-butyl alcohol (100 m1.). Most of the excess butyl alcoholwas then distilled out at a final pressure of 30 mm. and bathtemperatureof C. The

'' residual cake was cooled and broken up and din-butyl carbonate (250ml.) was added. The remainder of the excess butyl alcohol was thenfractionated out at 30 mm. and a bath temperature of 120-130 C. Themixture was then cooled to 100 C. and di-n-butyl ethylmalonate (49 g.)was added. During one hour, at a pressure of 30 mm. and bath temperatureof 120-130" 0., there was fractionated out 20 m1. of n-butyl alcohol.The mixture was then refluxed at a bath The mixture was then cooled andworked up as in Example 1.

There was recovered 38% (18.5 g.) of the din-butyl ethylmalonate andthere was obtained a 42% (25.5 g.) yield of di-n-butylethylbutylmalonate. This is a, 68% yield based on the din-butylethylmalonate actually consumed. The di-n-butyl ethylbutylmalonate had aboiling point of 117-119 C. at 1 mm. pressure and an n 26.5/D of1.4324-1.4329. The ester was identified by hydrolyzing it to obtainethylbutylmalonic acid, which melted at 116-117 C.

EXAMPLE 5 Isobutylation of di-isobutyl ethylmalonate Sodium (4.6 g.) wasreacted with isobutyl alcohol (100 ml.) Then the excess isobutyl alcoholwas vacuum distilled out until a mush remained. Then di-isobutylcarbonate (200 ml.) and di- 180-190 C. for four hours.

45% (26.5 g.) yield of di-isobutyl ethylisobutylmalonate. This is a 70%yield based on the di-isobutyl ethylmalonate actually consumed.

The boiling point of thedi-isobutyl ethylisobutylmalonate was 175 C. atmm., and the n 26.5/D I was 1.4320. The ester was identified by hydro-16lyzing it to obtain ethylisobutylmalonic acid. which melted at 109-110C.v The equivalent weight was found to be 94 (theory 96).

. E'xammr: 6

Isoamylation of di-isoamyl ethylmalonate .Potassium (7.6 g.) was reactedwith isoamyl alcohol (100 1:11.). Most of the excess isoamyl alcohol wasvacuum distilled out. To the cooled mushy residue were added di-isoamylcarbonate (200 ml.) and di-isoamyl ethylmalonate g.). Then the mixturewas vacuum fractionated at 28 mm. until all of the isoamyl alcohol hadbeen removed. The mixture was then stirred at atmospheric pressure and abath temperature of The mixture was then cooled and worked up asdescribed in Example 1.

There was obtained a (42 5.) yield of diisoamyl isoamylethylmalonate.The boiling point of the ester was 126-129 C. at 1 mm. pressure and the11. 26/D was 14351-14359. The

ester was identified by hydrolyzing it to obtain isoamylethylmalonicacid which melted at 120- e121 0'. and had an equivalent weight of 103(theory 101) EXAMPLE 7 Ethylation of diethyl n-octylmalonate moved.Then'the mixture wasifefiuxed at a bath temperature of 155-160 C. for4.5 hours. It was then cooled and worked up as described in Example 1.I'here was recovered 30%- (9 g.) of diethyl octylmalonate and there wasobtained a 33% (10 g.), yield of diethyl ethyloctylmalonate. This is a50% yield based on the diethyl octylmalonate actually consumed. Theboilingpoint of the diethyl,ethylmztylmaldnate was 122 C. at

1.5 mm. pressure and the n 26/Dwas 1.4334- 1.4336. The ester wasidentified by hydrolyzing umn. The mixture was stirred and heated to abath temperature of ISO-200 C. at a pressure of 5 mm. During two hours60 ml. of distillate was collected ata column head temperature of C. Themixture was then refluxed four hours'at the bath temperature of l-200 C.4

The mixture was then cooled and worked up as described in Example 1. Thedibenzyl carbonate was distilled oil through a column at reducedpressure and then the residue was distilled from a Claisen flask. Therewas obtained a- 53% (46 g.) yield of dibenzyl ethylbenzylmalonate ofboiling point 245-247" C. at 2 mm. pressure and n 235/13 of 1.5560. Thisester was identified by hydrolyzing it to obtain ethylbenzylmalonicacid, which melted at 125-127 C. and had an equivalent weight of 112(theory EXAMPLE 9 n-Butylation of di-n-butyl benzylmalonate Potassium(5.5 g.) was reacted with n-butyl alcohol (100 ml.) and most of theexcess n-butyl alcohol was vacuum distilled off. The solid residue wascooled and broken up and di-n-butyl benzylmalonate (43 g.) anddi-n-butyl carbonate (200 ml.) were added to it. Then the mixture wasvacuum fractionated at 28 mm. pressure and a bath temperature of C.untilall of the 'n-butyl alcohol was distilled out. Then the mixture wasstirred at atmospheric pressure and a bath temperature of 180-190 C. forfour hours. The mixture was cooled and worked up as described in Example1; There was obtained an 80% (37 "g.) yield of di-n-butylbutylbenzylmalonate of boiling point 172 C. at 3 mm. pressure and havingn 25.5/D of 1.4770. The ester was identified by hydrolyzing it to obtainbutyibenzylmalonic acid, which melted at 105-107 C. and had anequivalent weight of 127 (theory EXAMPLE 10 Alkylation ofdi-diethylcarbinyl ethyl-malonate with di-diethylcarbinyl carbonatePotassium (6.5 g.) was reacted with diethyl carbinol (125 ml.) andtheexcess carbinol was vacuum'distilled out until a gummy residue wasobtained.

Then di-diethylcarbinyl carbonate (200 ml.) and di-diethylcarbinylethylmalonate (45 g.) were added. The mixture was stirred and heated andthe remaining original carbinol and that pro-- duced by the reactionwere vacuum distilled out.

. -The mixture was then stirred at atmospheric pressure and at a bathtemperature of 180-190 C. for six hours. The mixture was cooled andworked up as usual. There was obtained a 35% (16 g.) yield ofdi-diethylcarbinyl diethylcarbinylethylmalonate.

EXAMPLE 11 Ethylatlon of diethyl .isopropylmalonate The sodio derivativeof diethyl isopropylmalonate was prepared from ethyl isovalerate, byreaction with diethyl carbonate, as described in the it toobtainethyloctylmalonic acid, which melted copendmg application of wamngmrdand at 82-83" C., and had an equivalent weight of 123 (theory 122).

. Exurrrr 8 Benn lotion of dibenzylethulmalonate A mixture was made orbenzyl alcohol (25 ml.), sodium methylate (10.8 3.), dibenzyl carbonate.(200 ml.) and dibenzyl ethylmalonate (62 g.) in

a 500 cc., three-necked flask, arranged with a the diethyl carbonate toproduce-diethyl ethylisopropylmalonate.

A mixture was made of sodium ethylate (27 g.) anddiethyl carbonate (300ml.) as described in Example 1. Then ethyl isovalerate (52 g.) wasadded. The mixture was stirred at atmospheric pressure and a bathtemperature of -175 C. and low boiling material (27 ml.), mostlyalcohol, was slowly fractionated out during twelve hours. cooledandworked up as described in Example 1. There was obtained a (9 g.)yield of diethyl ethylisopropylmalonate, boiling point 112-114" C. at 18mm. pressure. This ester was identified by hydrolyzing it toethylisopropylmalonic acid, which melted at 132-l34 C.

EXAMPLE 12 Emulation of diethyl ethlllmalonate The magnesio derivativeof .diethyl ethylmalonate was prepared from magnesium turnings (12g.),diethyl ethylmalonate (94 g.), anhydrous alcohol (60 ml.), andbenzene ml.) using carbon tetrachloride (1 ml. )as a catalyst,,followingwell known procedures. After the reaction was complete, diethylcarbonate (400 ml.) was added and the alcohol, benzene, and part of thediethyl carbonate (170 cc. total distillate) was fractionated out underreduced pressure.

The resulting diethyl carbonate solution of diethylmagnesio-ethylmalonate was placed in a steel bomb, and heated eighthours at a bath temperature of 220-225 C., at a pressure of 80 to 120lbs. After cooling, the reaction mixture was poured into an equal volumeof water, and made just acid with dilute hydrochloric acid. The oil wasseparated, washed with water, dried and fractionated. There was obtaineda 22% recovery of diethyl ethylmalonate and a yield of diethyldiethylmalonate, which represented about a yield on the basis of thediethyl ethylmalonate actually consumed. The diethyl diethylmalonat'eboiled at 109-111" C. at 15 mm. pressure. a

. Exxurnr 13 Butylation of di-n-butyl cetyl nal'onate Sodium butylatesolution prepared from n-butyl The mixture was then tion mixture wasmade slightly acid with dilute acetic acid, the oily layer was separatedand fractionated. A 30% yield (18 g.) of diethyl phenylethylmalonate,identified by boiling point and refractive index was obtained. Themelting point was found to be -9 to 7 C.

As indicated in the foregoing examples, the

metallo compound can be prepared separately} and then alkylated oraralkylated in accordance with the present invention. Alternatively, themetallo compound can be prepared, for example, in accordance with themethod described in the copending application of Wallingford andHomeyer,'S'erial No. 374,254, filed January 13, 1941, and the productwithout isolation may be alkylated or aralkylated in situ. The latteralternative of courseobviates any recovery of the malonate or themetallo derivative of the malonate prior to alkylatlon.

Typical of the metallo derivatives which have been found suitable arethe alkali metals, the alkaline earth metals, and aluminum.

It has been found that in most instances the alkylation or 'aralkylationshould be carried out at a temperature of at least C. Increasing thetemperature seems to increase the rate of reaction. Temperaturessubstantially lower than 100 C. do not give an appreciable yield ofalkylated or aralkylated compound in a reasonable time. Fo mostpurposes, a temperature substantially in excess of 100 C. is preferred.

In view of the above, it will be seen that the several objects of theinvention are achieved and other advantageous results attained.

As many changes could be made in the above processes without departingfrom the scope of the invention, it is intended that all mattercontained in the above description shall be interpreted as illustrativeand not in a limiting sense.

w What is claimed is:

alcohol and 2.9 g. of sodium was vacuum evaporated until a thick mushremained and to this cooled residue was added di-n-butyl cetylmalonate(55 g.) and di.-n-butyl carbonate ml).

. On warming and stirring the sodium butylate dis:- solved completely.Butyl alcohol was removed composed with water, neutralized with aceticacid,

the oil was separated, washed, dried and distilled. There was obtained ayield of 52 g. (83%) of di-n-butyl butylcetylmalonate boiling at 265-268 C at 4 mm. pressure and having n 20/D 1.4490 to 1.4502. The esterwas converted to butylcetylmalonic acid by saponiflcation with sodiumhydroxide, followed by acidification, and the acid was purified bycrystallization from petroleum ether. It melted at 97-985 C.

v Emma: 14 Emulation of 'diethfll phenillmalonate The sodio derivativeof diethyl phenylmalonate was prepared from sodium ethylate(equivalent 1. The method of alkylating a metallo derivative of amono-substituted malonic ester selected from the group consisting ofalkali metal, alkaline earth metal and aluminum derivatives whichcomprises reacting the derivative with a dialkyl carbonate.

to 5.8 g. sodium) and diethyl phenylmalona'te (59 ing, the pressurewas-30 lbs. and was due to carbon dioxide. This was vented and thereaction was heated for eight hours more, the final pressure being lbs.After cooling; the reac 2. The method of alkylating a malonic ester ofthe type R-C(M)(CO:R'):, in which R is selected from alkyl, aryl andaralkyl radicals,

R is selected from alkyl and aralkyl radicals, and M is an alkali metal,which comprises reactins the ester with a dialkyl carbonate.

3. The method of alkylating a malonic ester of the type R-C(M) (CO2R)2,in which R is an organic group attached by an aliphatic linkage, R. isselected from alkyl. and aralkyl radicals, and M is a -metal selectedfrom the group consisting of alkali metals, alkaline earth metals andaluminum, which comprises reacting the ester with a dialkyl carbonate.

4. The method of alkylating a malonic ester of the type R-C(M) (COzR')2, in which R is selected from alkyl, aryl and aralkyl radicals, R isselected from alkyl and aralkyl radicals, and M is selected from thegroup' consisting of alkali metals, alkaline earth metals and aluminum,which comprises reacting the ester with a dialkyl carbonate.

5. The method of alkylating a malonic ester of the type R-C(M) (COzR/M,in which R is an organic group attached by an aliphatic linkage, R isselected from alkyl and aralkyl radicals,

and M is an alkalimetal, which comprises reacting the ester with adialkyl carbonate.

6. The method which comprises reacting a 8. The method of alkylating' amalcnic ester.

of the type R-C(M) (COzR')2. in which R is selected fromalkyl, aryl andaralkyl radicals, R is selected from alkyl and aralkyl radicals, and Mis an alkali metal, which comprises reacting the ester with a dialkylcarbonate and distilling the product alcohol from the reaction mixture.

9. The method of alkylating a malonic ester of the type R-C(M) (CO2R')2,in which R is an organic group attached by an aliphatic linkage,

R is selected from alkyl and aralkyl radicals.

and M is an alkaline earth metal, which comprises reacting the esterwith a dialkyi carbonate.

. DAVID M. JONES.

